Pubmed du 06/05/20

mercredi 6 mai 2020

1. Parent and Provider Perspectives on the Diagnosis and Management of Autism in a Chinese Immigrant Population : Erratum. J Dev Behav Pediatr. 2020 ; 41(4) : 298.

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2. Cai DC, Wang Z, Bo T, Yan S, Liu Y, Liu Z, Zeljic K, Chen X, Zhan Y, Xu X, Du Y, Wang Y, Cang J, Wang GZ, Zhang J, Sun Q, Qiu Z, Ge S, Ye Z, Wang Z. MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys : Neural Mappings to Patients with Autism. J Neurosci. 2020 ; 40(19) : 3799-814.

MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene-circuit-behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis ; 3 females) and 20 wild-type monkeys (Macaca fascicularis ; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced beta-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene-circuit-behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2 However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.

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3. Ciarrusta J, Dimitrova R, Batalle D, O’Muircheartaigh J, Cordero-Grande L, Price A, Hughes E, Kangas J, Perry E, Javed A, Demilew J, Hajnal J, Edwards AD, Murphy D, Arichi T, McAlonan G. Emerging functional connectivity differences in newborn infants vulnerable to autism spectrum disorders. Translational psychiatry. 2020 ; 10(1) : 131.

Studies in animal models of autism spectrum disorders (ASD) suggest atypical early neural activity is a core vulnerability mechanism which alters functional connectivity and predisposes to dysmaturation of neural circuits. However, underlying biological changes associated to ASD in humans remain unclear. Results from functional connectivity studies of individuals diagnosed with ASD are highly heterogeneous, in part because of complex life-long secondary and/or compensatory events. To minimize these confounds and examine primary vulnerability mechanisms, we need to investigate very early brain development. Here, we tested the hypothesis that brain functional connectivity is altered in neonates who are vulnerable to this condition due to a family history of ASD. We acquired high temporal resolution multiband resting state functional magnetic resonance imaging (fMRI) in newborn infants with and without a first-degree relative with ASD. Differences in local functional connectivity were quantified using regional homogeneity (ReHo) analysis and long-range connectivity was assessed using distance correlation analysis. Neonates who have a first-degree relative with ASD had significantly higher ReHo within multiple resting state networks in comparison to age matched controls ; there were no differences in long range connectivity. Atypical local functional activity may constitute a biomarker of vulnerability, that might precede disruptions in long range connectivity reported in older individuals diagnosed with ASD.

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4. Del Valle Rubido M, Hollander E, McCracken JT, Shic F, Noeldeke J, Boak L, Khwaja O, Sadikhov S, Fontoura P, Umbricht D. Correction to : Exploring Social Biomarkers in HighFunctioning Adults with Autism and Asperger’s Versus Healthy Controls : A CrossSectional Analysis. J Autism Dev Disord. 2020.

The original version of this article unfortunately contained a mistake in CI values in Table 2.

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5. Fung LK, Flores RE, Gu M, Sun KL, James D, Schuck RK, Jo B, Park JH, Lee BC, Jung JH, Kim SE, Saggar M, Sacchet MD, Warnock G, Khalighi MM, Spielman D, Chin FT, Hardan AY. Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Mol Psychiatry. 2020.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [(18)F]flumazenil positron emission tomography ([(18)F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy ((1)H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, (1)H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

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6. Geryk J, Krsicka D, Vlckova M, Havlovicova M, Macek M, Jr., Kremlikova Pourova R. The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders : An In Silico Analysis. Metabolites. 2020 ; 10(5).

Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (GART, PFAS, PPAT, PAICS, ATIC, and ADSL) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis.

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7. Granovetter MC, Burlingham CS, Blauch NM, Minshew NJ, Heeger DJ, Behrmann M. Uncharacteristic Task-Evoked Pupillary Responses Implicate Atypical Locus Ceruleus Activity in Autism. J Neurosci. 2020 ; 40(19) : 3815-26.

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.

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8. Hao Y, Franco JH, Sundarrajan M, Chen Y. A Pilot Study Comparing Tele-therapy and In-Person Therapy : Perspectives from Parent-Mediated Intervention for Children with Autism Spectrum Disorders. J Autism Dev Disord. 2020.

Conclusions about the efficacy of tele-therapy for parent-mediated intervention for children with Autism Spectrum Disorders (ASD) are limited, due to the shortage of direct comparisons between tele-therapy and traditional face-to-face therapy. In this study, we implemented a parent training program, which targeted on language facilitating intervention strategies. Fifteen parents of children with ASD participated in person, and 15 participated via online video conferencing. We measured parents’ intervention fidelity and children’s initiations, responses, lexical diversity and morphosyntactic complexity. Results indicated significant improvements in parents’ fidelity and children’s lexical diversity and morphosyntactic complexity. No significant differences were detected between the two therapy delivery groups on any outcome measures. Finally, children’s progress on morphosyntactic complexity was significantly correlated with parents’ improvement on fidelity.

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9. Henriksen AD, Andrade A, Harris EP, Rissman EF, Wolstenholme JT. Bisphenol a Exposure in Utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling. International journal of molecular sciences. 2020 ; 21(9).

Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell-cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.

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10. Hosozawa M, Sacker A, Mandy W, Midouhas E, Flouri E, Cable N. Determinants of an autism spectrum disorder diagnosis in childhood and adolescence : Evidence from the UK Millennium Cohort Study. Autism. 2020 : 1362361320913671.

This study aimed to identify determinants of a late autism spectrum disorder diagnosis, including diagnoses made ’very late’ (i.e., in adolescence), using the Millennium Cohort Study, a nationally representative population-based cohort in the United Kingdom. Children diagnosed with autism spectrum disorder by age 14 (N = 581) were included and grouped by the parent-reported timing of diagnosis : before school (up to age 5), during primary school (age 5-11) and during secondary school (age 11-14). Predictors of diagnostic timing, at the child, family and school levels, were investigated using multinomial logistic regression. Most (79%) children with autism spectrum disorder were diagnosed after school entry, and 28% were not diagnosed until secondary school. Among those not diagnosed until secondary school, 75% had been identified at age 5 years by a parent and/or teacher as having socio-behavioural difficulties. Being diagnosed after starting school was predicted by living in poverty (adjusted relative risk ratio : primary = 1.90, 95% confidence interval : 1.03-3.53 ; secondary = 2.15, 1.05-4.42) and/or having no initial parental concerns (primary = 0.32, 0.15-0.70 ; secondary = 0.19, 0.09-0.43). Having typical-range intelligence also predicted diagnosis during secondary school. The result indicates that those without cognitive delays and poorer children were at risk of ’very late’ (i.e. adolescent) diagnosis. Strategies to promote earlier identification, targeting age at primary school entry, could help those more likely to be diagnosed late. Lay abstract Despite policy emphasis on early identification, many children with autism spectrum disorder are diagnosed late, with some being diagnosed as late as in adolescence. However, evidence on what determines the timing of autism spectrum disorder diagnosis including children diagnosed in adolescence is lacking. Understanding these determinants, particularly in those diagnosed later than is ideal, can inform the development of effective strategies to improve earlier identification of autism spectrum disorder. This study used a nationally representative population-based cohort in the United Kingdom to explore child, family and school level predictors of timing of autism spectrum disorder diagnosis. In the United Kingdom, 79% of the children with autism spectrum disorder were diagnosed after entering primary school and 28% during secondary school. Among those not diagnosed until secondary school, 75% had shown social difficulties noticed by parents and/or teachers at age 5 years. The results suggest that healthcare providers should be aware that, even for universal systems of care, those living in poverty and having higher intelligence are most likely to miss out on a timely diagnosis. Strategies to promote earlier identification among school-aged children, including targeting primary school entry age (i.e. around age 5) and that encouraging referrals for a formal assessment at the first report of concerns over the child’s social development may benefit those children who would otherwise be diagnosed later.

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11. Kozhemiako N, Nunes AS, Vakorin V, Iarocci G, Ribary U, Doesburg SM. Alterations in Local Connectivity and Their Developmental Trajectories in Autism Spectrum Disorder : Does Being Female Matter ?. Cereb Cortex. 2020.

Autism spectrum disorder (ASD) is diagnosed more often in males with a ratio of 1:4 females/males. This bias is even stronger in neuroimaging studies. There is a growing evidence suggesting that local connectivity and its developmental trajectory is altered in ASD. Here, we aim to investigate how local connectivity and its age-related trajectories vary with ASD in both males and females. We used resting-state fMRI data from the ABIDE I and II repository : males (n = 102) and females (n = 92) with ASD, and typically developing males (n = 104) and females (n = 92) aged between 6 and 26. Local connectivity was quantified as regional homogeneity. We found increases in local connectivity in participants with ASD in the somatomotor and limbic networks and decreased local connectivity within the default mode network. These alterations were more pronounced in females with ASD. In addition, the association between local connectivity and ASD symptoms was more robust in females. Females with ASD had the most distinct developmental trajectories of local connectivity compared with other groups. Overall, our findings of more pronounced local connectivity alterations in females with ASD could indicate a greater etiological load for an ASD diagnosis in this group congruent with the female protective effect hypothesis.

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12. Lenart J, Bratek E, Lazarewicz JW, Zieminska E. Changes in the Expression of SNAP-25 Protein in the Brain of Juvenile Rats in Two Models of Autism. Journal of molecular neuroscience : MN. 2020.

The results of genetic studies suggest a possible role for SNAP-25 polymorphism in the development of autism spectrum disorders (ASDs) ; however, there are no data available on whether changes in SNAP-25 expression also affect animals in rodent models of ASD. The aim of the present study was to explore this issue. The studies included 1-month-old rats representing valproic acid (VPA)- and thalidomide (THAL)-induced models of autism. Their mothers received single doses of VPA (800 mg/kg) or THAL (500 mg/kg) per os on the 11th day of gestation. SNAP-25 protein content in the cerebellum, hippocampus, and frontal lobe was determined using Western blotting, while changes of mRNA levels of Snap25 gene were determined using real-time polymerase chain reaction. Compared to controls, SNAP-25 content was decreased by approximately 35% in all brain structures tested, in both males and females, exclusively in the VPA group. In contrast to this, Snap25 expression, studied in males, was increased in the hippocampus and cerebellum in both, VPA- and THAL-treated rats. We discuss the compliance of these results with the hypothesized role of SNAP-25 in the pathophysiology of ASD and the adequacy of the experimental models used.

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13. Melogno S, Pinto MA, Ruzza A, Scalisi TG. Improving the Ability to Write Persuasive Texts in a Boy with Autism Spectrum Disorder : Outcomes of an Intervention. Brain Sci. 2020 ; 10(5).

In this paper, we describe an intervention implemented to assist a 13.2-year-old boy with Autism Spectrum Disorder, G, without intellectual disability, aimed at improving his ability to compose persuasive texts. There was an initial assessment (baseline), an intermediate assessment after two weeks, a six-session intervention phase, and a post-intervention assessment. Our intervention applied two procedures. The first aimed at enhancing general composition abilities in terms of picking (P) ideas, organizing (O) notes, and writing (W) them down (POW), while the second specified the steps to write a persuasive text addressing a possible reader : a topic sentence (T), reasons (R), an explanation (E) for the reasons and the end of the sentence (E) (TREE). These procedures were termed POW + TREE. To analyze G’s texts, three types of measures were used by two raters at baseline, intermediate and post-test time : (a) the presence of the TREE components ; (b) the quality of the reasons and explanations for the reasons ; (c) the number of mental state terms. All these measures showed relevant quantitative improvements, as well as qualitative changes. In addition, when G’s performance at the end of the intervention was compared to that of typically developing controls, no statistical difference appeared. The results are discussed in light of the potentialities offered by the type of intervention described here.

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14. Modi ME, Sahin M. Tau : A Novel Entry Point for mTOR-Based Treatments in Autism Spectrum Disorder ?. Neuron. 2020 ; 106(3) : 359-61.

Dysregulation of the PI3K/Akt/mTOR pathway has become a point of convergence in autism spectrum disorder (ASD). In this issue of Neuron, Tai et al. (2020) identify a therapeutic role for tau reduction in downregulating this pathway and ameliorating ASD-like symptoms.

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15. Ogruc Ildiz G, Bayari S, Karadag A, Kaygisiz E, Fausto R. Fourier Transform Infrared Spectroscopy Based Complementary Diagnosis Tool for Autism Spectrum Disorder in Children and Adolescents. Molecules (Basel, Switzerland). 2020 ; 25(9).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that begins early in life and continues lifelong with strong personal and societal implications. It affects about 1%-2% of the children population in the world. The absence of auxiliary methods that can complement the clinical evaluation of ASD increases the probability of false identification of the disorder, especially in the case of very young children. In this study, analytical models for auxiliary diagnosis of ASD in children and adolescents, based on the analysis of patients’ blood serum ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) spectra, were developed. The models use chemometrics (either Principal Component Analysis (PCA) or Partial Least Squares Discriminant Analysis (PLS-DA)) methods, with the infrared spectra being the X-predictor variables. The two developed models exhibit excellent classification performance for samples of ASD individuals vs. healthy controls. Interestingly, the simplest, unsupervised PCA-based model results to have a global performance identical to the more demanding, supervised (PLS-DA)-based model. The developed PCA-based model thus appears as the more economical alternative one for use in the clinical environment. Hierarchical clustering analysis performed on the full set of samples was also successful in discriminating the two groups.

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16. Pangrazzi L, Balasco L, Bozzi Y. Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders. International journal of molecular sciences. 2020 ; 21(9).

Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD.

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17. Renard E, Leheup B, Gueant-Rodriguez RM, Oussalah A, Quadros EV, Gueant JL. Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 2020.

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL(R)) at a lower dose of 5mg twice daily. Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P=0.003, P=0.004 and P=0.022, respectively), but not in the placebo group (P=0.574, P=0.780, P=0.269, respectively). We observed a greater change of ADOS global score (-2.78 vs. -0.4 points) and (-1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed. This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.

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18. Rose BI, Brown SE. An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency. Journal of assisted reproduction and genetics. 2020.

Fragile X and fragile X-associated tremor-ataxia syndrome (FXTAS) are caused by mutations of the FMR1 gene. The mutations causing FXTAS can expand in a generation to a "full mutation" causing fragile X syndrome. The mutations causing FXTAS and the phenotype, fragile X-associated premature ovarian insufficiency (FXPOI), are referred to as the FMR1 premutation (PM). The objective of this paper was to formulate a theory to explain the Mechanism for FXPOI.Recent research on fragile X syndrome and FXTAS has led to sophisticated theories about the mechanisms underlying these diseases. It has been proposed that similar mechanisms underlie FXPOI. Utilizing recent research on FXTAS, but a more detailed application of ovarian physiology, we present a more ovarian specific theory as to the primary mechanism explaining the development of FXPOI.The FXPOI phenotype may best be viewed as derivative of the observation that fragile X PM carriers experience menopause an average of 5 years earlier than non-carriers. Women carrying the PM experience an earlier menopause because of an accelerated activation of their primordial follicle pool. This acceleration of primordial follicle activation occurs, in part, because of diminished AMH production. AMH production is diminished because of accelerated atresia of early antral follicles. This accelerated atresia likely occurs because the fragile X PM leads to a slowing of the rate of granulosa cell mitosis in some follicles.

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19. Shield A, Igel M, Randall K, Meier RP. The Source of Palm Orientation Errors in the Signing of Children with ASD : Imitative, Motoric, or Both ?. Brain Sci. 2020 ; 10(5).

Palm orientation reversal errors (e.g., producing the ’bye-bye’ gesture with palm facing inward rather than outward as is customary in American culture) have been documented in the signing of deaf and hearing children with autism spectrum disorder (ASD) and in the imitation of gestures by signing and non-signing children with ASD. However the source of these unusual errors remains opaque. Given that children with ASD have documented difficulties with both imitation and motor skills, it is important to clarify the nature of these errors. Here we present a longitudinal case study of a single child with ASD, a hearing, signing child of Deaf parents. Samples of the child’s signing were analyzed at ages 4 ;11, 6 ;2, 10 ;2, and 14 ;11. Lexical signs and fingerspelled letters were coded for the four parameters of sign articulation (handshape, location, movement, and palm orientation). Errors decreased for handshape, location, and movement after age 4 ;11, but increased on palm orientation from 4 ;11 and remained high, exceeding 55% of signs by 14 ;11. Fingerspelled letters contained a large proportion of 180-degree reversals, which suggest an origin in imitation differences, as well as midline-facing errors, suggestive of a motor origin. These longitudinal data suggest that palm orientation errors could be rooted in both imitation differences and motoric difficulties.

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20. Strang JF, Knauss M, van der Miesen A, McGuire JK, Kenworthy L, Caplan R, Freeman A, Sadikova E, Zaks Z, Pervez N, Balleur A, Rowlands DW, Sibarium E, Willing L, McCool MA, Ehrbar RD, Wyss SE, Wimms H, Tobing J, Thomas J, Austen J, Pine E, Griffin AD, Janssen A, Gomez-Lobo V, Brandt A, Morgan C, Meagher H, Gohari D, Kirby L, Russell L, Powers MD, Anthony LG. A Clinical Program for Transgender and Gender-Diverse Neurodiverse/Autistic Adolescents Developed through Community-Based Participatory Design. J Clin Child Adolesc Psychol. 2020 : 1-16.

Objective : A series of studies report elevated rates of autism and autistic characteristics among gender-diverse youth seeking gender services. Although youth with the co-occurrence present with complex care needs, existing studies have focused on co-occurrence rates. Further, clinical commentaries have emphasized provider-centered interpretations of clinical needs rather than key stakeholder-driven clinical approaches. This study aimed to employ community-based participatory research methodologies to develop a key stakeholder-driven clinical group program.Method : Autistic/neurodiverse gender-diverse (A/ND-GD) youth (N = 31), parents of A/ND-GD youth (N = 46), A/ND-GD self-advocates (N = 10), and expert clinical providers (N = 10) participated in a multi-stage community-based participatory procedure. Needs assessment data were collected repeatedly over time from A/ND-GD youth and their parents as the youth interacted with one another through ongoing clinical groups, the curriculum of which was developed progressively through the iterative needs assessments.Results : Separate adolescent and parent needs assessments revealed key priorities for youth (e.g., the importance of connecting with other A/ND-GD youth and the benefit of experiencing a range of gender-diverse role models to make gender exploration and/or gender affirmation more concrete) and parents (e.g., the need for A/ND-related supports for their children as well as provision of an A/ND-friendly environment that fosters exploration of a range of gender expressions/options). Integration and translation of youth and parent priorities resulted in 11 novel clinical techniques for this population.Conclusions : With generally high acceptability ratings for each component of the group program, this study presents a community-driven clinical model to support broad care needs and preferences of A/ND-GD adolescents.

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21. Tai C, Chang CW, Yu GQ, Lopez I, Yu X, Wang X, Guo W, Mucke L. Tau Reduction Prevents Key Features of Autism in Mouse Models. Neuron. 2020 ; 106(3) : 421-37.e11.

Autism is characterized by repetitive behaviors, impaired social interactions, and communication deficits. It is a prevalent neurodevelopmental disorder, and available treatments offer little benefit. Here, we show that genetically reducing the protein tau prevents behavioral signs of autism in two mouse models simulating distinct causes of this condition. Similar to a proportion of people with autism, both models have epilepsy, abnormally enlarged brains, and overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/ mammalian target of rapamycin (mTOR) signaling pathway. All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau. We identify disinhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative PI3K regulator that tau controls, as a plausible mechanism and demonstrate that tau interacts with PTEN via tau’s proline-rich domain. Our findings suggest an enabling role of tau in the pathogenesis of autism and identify tau reduction as a potential therapeutic strategy for some of the disorders that cause this condition.

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22. Taylor MJ, Rosenqvist MA, Larsson H, Gillberg C, D’Onofrio BM, Lichtenstein P, Lundstrom S. Etiology of Autism Spectrum Disorders and Autistic Traits Over Time. JAMA Psychiatry. 2020.

Importance : The frequency with which autism spectrum disorders (ASDs) are diagnosed has shown a marked increase in recent years. One suggestion is that this is partly because of secular changes in the environment, yet to our knowledge this hypothesis lacks evidence. Objective : To assess whether the relative importance of genetic and environmental associations with ASD and autistic traits has changed over a 16-year and 26-year period. Design, Setting, and Participants : A twin design was used to assess whether the heritability of ASD and autistic traits has changed over time. Data from 2 nationwide Swedish twin cohorts was used : the Swedish Twin Registry (STR ; participants born between January 1982 and December 2008) and the Child and Adolescent Twin Study in Sweden (CATSS ; participants born between January 1992 and December 2008). Autism spectrum disorder diagnoses were identified for twins in the STR, with follow-up to 2013. Questionnaires assigned screening diagnoses of ASD to CATSS participants and assessed autistic traits. Analyses were performed from September 1, 2018, to March 31, 2019. Exposures : Each sample was divided into several birth cohorts covering 1982 to 1991 (for the STR only), 1992-1995, 1996-1999, 2000-2003, and 2004-2008. Outcomes : We assessed whether the genetric and environment variance underlying autistic traits changed across birth cohorts and examined whether the relative contribution of genetics and environment to liability for autism changed across birth cohorts. Results : Data were available for 22678 twin pairs (5922 female same-sex pairs [26.1%], 5563 male same-sex pairs [24.5%], and 11193 opposite-sex pairs [49.4%]) in the STR and 15280 pairs (4880 female same-sex pairs [31.9%], 5092 male same-sex pairs [33.3%], and 5308 opposite-sex pairs [34.7%]) in CATSS. The heritability of ASD diagnoses in the STR ranged from 0.88 (95% CI, 0.74-0.96) to 0.97 (95% CI, 0.89-0.99). The heritability of screening diagnoses in CATSS varied from 0.75 (95% CI, 0.58-0.87) to 0.93 (95% CI, 0.84-0.98). Autistic traits showed a modest variance increase over time that was associated with increases in genetic and environmental variance, with the total variance increasing from 0.95 (95% CI, 0.92-0.98) to 1.17 (95% CI, 1.13-1.21) over time. Conclusions and Relevance : Weak evidence was found for changes in the genetic and environmental factors underlying ASD and autistic traits over time. Genetic factors played a consistently larger role than environmental factors. Environmental factors are thus unlikely to explain the increase in the prevalence of ASD.

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23. Valori I, Bayramova R, McKenna-Plumley PE, Farroni T. Sensorimotor Research Utilising Immersive Virtual Reality : A Pilot Study with Children and Adults with Autism Spectrum Disorders. Brain Sci. 2020 ; 10(5).

When learning and interacting with the world, people with Autism Spectrum Disorders (ASD) show compromised use of vision and enhanced reliance on body-based information. As this atypical profile is associated with motor and social difficulties, interventions could aim to reduce the potentially isolating reliance on the body and foster the use of visual information. To this end, head-mounted displays (HMDs) have unique features that enable the design of Immersive Virtual Realities (IVR) for manipulating and training sensorimotor processing. The present study assesses feasibility and offers some early insights from a new paradigm for exploring how children and adults with ASD interact with Reality and IVR when vision and proprioception are manipulated. Seven participants (five adults, two children) performed a self-turn task in two environments (Reality and IVR) for each of three sensory conditions (Only Proprioception, Only Vision, Vision + Proprioception) in a purpose-designed testing room and an HMD-simulated environment. The pilot indicates good feasibility of the paradigm. Preliminary data visualisation suggests the importance of considering inter-individual variability. The participants in this study who performed worse with Only Vision and better with Only Proprioception seemed to benefit from the use of IVR. Those who performed better with Only Vision and worse with Only Proprioception seemed to benefit from Reality. Therefore, we invite researchers and clinicians to consider that IVR may facilitate or impair individuals depending on their profiles.

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24. Wang JG, Cai KL, Liu ZM, Herold F, Zou L, Zhu LN, Xiong X, Chen AG. Effects of Mini-Basketball Training Program on Executive Functions and Core Symptoms among Preschool Children with Autism Spectrum Disorders. Brain Sci. 2020 ; 10(5).

This study examined the effects of a 12-week mini-basketball training program (MBTP) on executive functions and core symptoms among preschoolers with autism spectrum disorder (ASD). In this quasi-experimental pilot study, 33 ASD preschoolers who received their conventional rehabilitation program were assigned to either a MBTP group (n = 18) or control group (n = 15). Specifically, the experimental group was required to take an additional 12-week MBTP (five days per week, one session per day, and forty minutes per session), while the control group was instructed to maintain their daily activities. Executive functions and core symptoms (social communication impairment and repetitive behavior) were evaluated by the Childhood Executive Functioning Inventory (CHEXI), the Social Responsiveness Scale-Second Edition (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R), respectively. After the 12-week intervention period, the MBTP group exhibited significantly better performances in working memory (F = 7.51, p < 0.01, partial eta(2) = 0.195) and regulation (F = 4.23, p < 0.05, partial eta(2) = 0.12) as compared to the control group. Moreover, the MBTP significantly improved core symptoms of ASD preschoolers, including the social communication impairment (F = 6.02, p < 0.05, partial eta(2) = 0.020) and repetitive behavior (F = 5.79, p < 0.05, partial eta(2) = 0.016). Based on our findings, we concluded that the 12-week MBTP may improve executive functions and core symptoms in preschoolers with ASD, and we provide new evidence that regular physical exercise in the form of a MBTP is a promising alternative to treat ASD.

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25. Woodbury-Smith M, Zarrei M, Wei J, Thiruvahindrapuram B, O’Connor I, Paterson AD, Yuen RKC, Dastan J, Stavropoulos DJ, Howe JL, Thompson A, Parlier M, Fernandez B, Piven J, Anagnostou E, Scherer SW, Vieland VJ, Szatmari P. Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees. Am J Med Genet B Neuropsychiatr Genet. 2020.

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD’s tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype ; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.

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26. Zhou MS, Nasir M, Farhat LC, Kook M, Artukoglu BB, Bloch MH. Meta-analysis : Pharmacologic Treatment of Restricted and Repetitive Behaviors in Autism Spectrum Disorders. J Am Acad Child Adolesc Psychiatry. 2020.

OBJECTIVE : To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD). METHOD : We searched PubMed, Embase, and CENTRAL to identify all double-blind, randomized, placebo-controlled trials that examined the efficacy of pharmacological agents in the treatment of autism spectrum disorders and measured restricted and repetitive behaviors as an outcome. Our primary outcome was standardized mean difference in rating scales of RRBs. RESULTS : We identified 64 randomized, placebo-controlled trials involving 3,499 participants with ASD. Antipsychotics significantly improved RRB outcomes compared to placebo [standardized mean difference (SMD)=0.28 (95% Confidence Interval (CI) : 0.08-0.49), z=2.77, p=0.01] demonstrating a small effect size. Larger significant positive effects on RRBs in ASD were seen in individual studies with fluvoxamine, buspirone, bumetanide, divalproex, guanfacine, and folinic acid that have not been replicated. Other frequently studied pharmacological treatments in ASD including oxytocin, omega-3 fatty acids, selective serotonin reuptake inhibitors (SSRI) and methylphenidate did not demonstrate significant benefit in reducing RRB compared to placebo [oxytocin : SMD=0.23 (95% CI : -0.01-0.47), z=1.85, p= 0.06 ; omega-3 fatty acids : SMD = 0.19 (95% CI : -0.05-0.43), z= 1.54, p = 0.12 ; SSRI : SMD=0.09 (95% CI : -0.21-0.39), z=0.60, p=0.56 ; methylphenidate : SMD=0.18 (95% CI : -0.11-0.46), z=1.23, p=0.22]. CONCLUSION : The results of the present meta-analysis suggest that currently available pharmacological agents have at best only a modest benefit for the treatment of RRBs in ASD with the most evidence supporting antipsychotic medications. Additional RCTs with standardized study designs and consistent and specific assessment tools for RRBs, are needed to further understand how we can best help ameliorate these behaviors in individuals with ASD.

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